The present invention relates to photocurable polysiloxanes polymers (silicones) having functional acryl groups, useful in the preparation of intraocular lenses (IOLs). The invention also relates to methods for producing elastomers comprising the said polymers, as well as to methods for producing accommodating lenses in vivo, which means that the lens is formed in the capsular bag of the eye.
Implantation of an intraocular lens (IOL) following the extraction of a cataract is now a standard ophthalmic procedure. The conventional IOL used to replace the natural lens is a fixed focus lens manufactured from a rigid plastic such as poly(methylmetliacrylate), PMMA, or from an elastomer, such as silicone. The implantation of such a lens usually necessitates the patient using spectacular correction for reading. To overcome this limitation of the conventional IOL, increasing attention has been given to bifocal and multizonal lenses.
The technique of cataract explanation and lens replacement for an accommodating IOL, an accommodating capsular lens. ACL, involves the metered injection of a low viscosity liquid, through a small incision (≈1 mm diameter), into the capsular bag, followed by its polymerization under forming pressure to create a lens of the required shape, using the form of the capsular bag as the mold. To reproduce the optical performance of the natural lens, the replacement lens will require a refractive index close to 1.41. To respond to the accommodating forces of the eye, the compression modulus of IOL should be comparable to that of the natural lens which is in the range of about 1 to 5 kPa. To design materials which balance the conflicting material""s requirements of the ACL requires the design of unique systems. These considerations have led a number of researchers to propose and to study the development of an ACL. An accommodative re-fill lens is an IOL formed by filling the capsular bag with the precursors of an elastomer, and causing, or allowing, the elastomer to set in the form of the natural lens. Thin-walled inflatable balloons, of silicone rubber, have also been developed which can be inserted into the capsular bag and filled with the desired system.
Most researchers of the development of the accommodative re-fill lens have used silicone-derived systems for filling the capsular bag, either in the form of silicone oils or LTV (low temperature vulcanizing) silicone elastomers. Such systems suffer from disadvantages in the context of re-fill lens formation, the dimethyl silicones have a restricted refractive index (1.40), LTVs cure slowly, up to 12 hours may be needed to complete their setting and their slow setting may result in material loss from the capsular bag through the surgical incision, further, the high viscosities of some silicone oils and intermediates make their air-bubble free injection very difficult.
Injectable formulations of polysiloxanes for making an IOL directly in the capsular bag of the human eye have been suggested in U.S. Pat. Nos. 5,278,258, 5,391,590 (""590) and 5,411,553 to Gerace et al as well as in U.S. Pat. No. 5,116,369 (Kushibiki et al) These patents describe mixtures of a vinyl-containing polyorganosiloxane, an organosilicone comprising hydride groups and a platinum group metal catalyst which are capable of being cured at ambient body temperature to an IOL inside the capsular bag of the eye. These compositions suffer from the general drawback of low temperature curing in that the curing process is difficult to control for the surgeon. The use of silicone fluids, demonstrating the principle of a silicone-based ACL, has been reported by Haefliger, E. and Parel, J-M. (1994) J. Refractive and Corneal Surgery 10, 550-555, but the gain in accommodation declined, probably because the system was not crosslinked.
Subsequently, the difficulties of introducing a thermally curing silicone into the capsular bag have been demonstrated. A major disadvantage of the use of a thermally curable system, such as one based on Pt-cured vinyl addition, for the xe2x80x9cmold-in-the-bagxe2x80x9d approach is understood from a consideration of the three characteristic phases of network formation, viz. (a) pre-gelation; (b) gelation; and (c) curing. A lens can only be molded successfully in the pre-gelation phase, and once the system has passed into its gelation phase it cannot be molded with precision. This is because the gel (polymer of infinite molecular weight) which is formed at and after the gel point has an elastic memory, and so, regardless of the forming conditions, it will always revert to its original shape with time. When molding an IOL, or ACL, this recovery process becomes evident as surface defects, such as ripples or wrinkles, which cause serious impairment of lens quality. When molding lenses from silicone systems, involving thermally induced polymerization, outside the body this phenomenon is easily regulated by adjusting the process variables of catalyst type and concentration, time, temperature and pressure. Molding an ACL within the eye during surgery imposes severe restrictions on the choice of these process variables, the molding temperature is body temperature, the molding time is the minimum compatible with the required residence time for any given patient upon the operating table, that is to say that ideally it must be variable to meet the exigencies of the surgical demands of both the ophthalmologist and the patient. In general terms, in a thermally cured silicone system, such as those based on Pt-catalysts, the durations of the pre-gelation and cure phases are coupled, a system with a short cure time has a short pre-gelation time. It is generally regarded as complicated to lengthen the pre-gelation time without lengthening the cure time.
To comply with the difficulties of controlling the thermally induced curing it would be desirable to provide systems wherein the curing is command set by the surgeon. For this purpose photocurable (i.e. photopolymerization) compositions have been contemplated. EP 0414219 describes an injectable system in which the liquid composition comprises a difunctional acrylate and/or methacrylate ester and a photo initiator activated by light of 400-500 nm wavelength Hettlich et al (German J. Ophthalmol. vol. 1, 346-349, 1992) was amongst the first to propose the use of photopolymerization of a monomer system as an alternative approach to setting the material within the capsular bag. He pointed to the clinical success of blue light photocurable resins for dental applications and explored the use of such systems as injectable materials for filling capsular bags from the eyes of cadaver pigs and live rabbits. However, the systems used by Hettlich form materials with moduli too high to allow accommodative processes. Further, the introduction of acrylic monomers into the eye would be undesirable, since they are well-known to have high physiological activity.
Compositions comprising polysiloxanes with functional acrylic end groups which are curable with UV light have earlier been disclosed for the manufacture of contact lenses. Curable acrylic silicones per se have indeed been known for a considerable time in various industrial applications, as disclosed by U.S. Pat. Nos. 4,778,862 and 4,348,454. U.S. Pat. No. 5,321,108 and the Japanese patent specifications published as 3-257420, 4-159319 and 5-164995 disclose compositions of acryl-terminated polysiloxanes suitable for contact lens production. However, the compositions for making contact lenses are unsuitable for intraocular lens production directly inside the human eye, wherein specific considerations to the polysiloxanes must be taken in order to perfect an injectable lens forming material.
Consequently, there is a need for photocurable polymers and injectable compositions thereof which are adapted to be included in a composition suitable for injection into the capsular bag of the human eye. The present invention aims to perfect such polymers and compositions including them, so they meet the necessary requirements for injectable lens materials.
It is an object of the present invention to provide photocurable polysiloxane copolymers which can be polymerized to intraocular lenses in the presence of visible light, in particular blue light.
It is a particularly important object to provide such polysiloxanes which are adapted for injection directly into the capsular sac of the human eye directly in connection to that the defect natural crystalline lens has been surgically removed.
It is another important object of the invention to provide compositions of said polysiloxanes together with a photoinitiator and further complementary additives necessary for forming the solid elastomer lens by final curing in the capsular sac.
In a general aspect the present invention relates to an polysiloxane copolymer having functional acryl groups which are capable of being photopolymerized into a solid intraocular lens with a specific gravity greater than about 1.0 and with a refractive index suitable for restoring the refractive power of the natural crystalline lens. For this purpose, the polysiloxane copolymer has siloxane monomer units are selected among substituted or unsubstituted arylsiloxanes, arylalkylsiloxanes, alkyl(alkyl)siloxanes of the general formula xe2x80x94RaRbSiOxe2x80x94. In order to accomplish suitably high refractive indices of the polysiloxane copolymer, it is preferable that one siloxane monomer unit is an arylsiloxane or an arylakylsiloxane, more preferably diphenyl siloxane or phenylmethylsiloxane. It is also highly preferred that said substitutions are fluorosubstitutions, in particular it is preferred that one siloxane monomer unit incorporates a fluroroalkyl group, more preferably one siloxane monomer is fluoroalkyl(alkyl)siloxane. According to a preferred aspect, the amount of fluoroalkyl(alkyl)siloxane units exceeds about 4 mol %. This enables a special advantage of the inventive polysiloxanes by providing them with higher specific gravity than conventional polysiloxanes reported in ophthalmic use.
Functional acryl groups are defined herein by that at the polysiloxane molecules have functional groups attached thereto including an acryl group moiety, so as to become acryl-bearing, by acryl attachment to the siloxane monomers of the polysiloxane backbone, its terminal ends, or both. The acryl groups in said functional groups can be linked to the silicone atoms by spacers. Examples of functional acryl groups include acrylamidopropyl, methacrylamidopropyl, acryloxyhexyl and methacryloxyhexyl. Preferably, the functional acryl groups are attached to the terminal ends of polysiloxane molecules, as exemplified by acrylamidopropyl-, methacrylamidopropyl-, acryloxyhexyl- and methacryloxyhexyl-terminated polysiloxanes. Those skilled in the art can consider numerous such alternatives which maintain the basic function of having an acryl group for subsequent crosslinking/polymerization of the polysiloxane molecules into larger network together with a photoinitiator. In the same manner it is also to be understood that the meaning of acryl group should include acryl or substituted acryl, such as methacryl, moieties attached through a variety of linkages including ester, amide and urethane linkages, or functional analogues of acryl capable of undergoing crosslinking reactions with a photoinitiator.
In a further aspect, the invention relates to a process for production of polysiloxane copolymer having functional acryl groups, as described above. Such a process is generally described in the Examples below and the skilled person will be able to make suitable modifications in order to prepare other copolymers within the scope of the invention.
The polysiloxane copolymers having functional acryl groups according to the present invention should preferably have a refractive index above about 1.39 in order to restore the refractive index of the natural lens which has a refractive index of about 1.41. It is an important aspect of the present invention to be able to control the refractive index of polysiloxanes by selection of its siloxane monomer composition and thereby the refractive outcome of the final implanted lens. It is to be understood that refractive indices can be up to about 1.60 is within the context of the present application if this is required for a specific optical application. This further considered in the co-pending International Patent Application with even filing date claiming priority from U.S. patent application Ser. No. 09/170,160 which hereby is incorporated as a reference.
According to a preferred aspect of the present invention, the polysiloxane copolymer having functional acryl groups can be obtained from a copolymer having the general formula: 
wherein R1 and R2 are independently C1-C6 alkyl; R3 is phenyl; R4 is phenyl or C1-C6 alkyl; R5 is CF3(CH2)x wherein x is 1-5; R6 is C1-C6 alkyl or fluoroalkyl; 1 is in the molar fraction range of 0 to 0.95; m is in the molar fraction range of 0 to 0.7; and n is in the molar fraction range of 0 to 0.65, the copolymer having functional acryl groups at the terminal ends thereof. In one embodiment, m is in the molar fraction range of from greater than 0 to 0.7; and n is in the molar fraction range of from greater than 0 to 0.65.
It is preferred that R1 is methyl, that R2 is methyl, R4 is phenyl, that x is 2, either independently, or in combination.
Preferably according to these alternatives R6 is methyl. According to one embodiment, the polysiloxane is a copolymer of diphenyl or phenylalkyl siloxane and dialkyl siloxane with terminal acryl groups. According to further embodiments, the polysiloxane is a copolymer of diphenyl or phenylalkyl siloxane and trifluoroalkyl(alkyl)siloxane, or a terpolymer or higher order polymer of diphenyl and/or phenylalkyl siloxane, dialkyl siloxane and trifluoroalkyl alkyl siloxane. According to a specific preferred embodiment, polysiloxane is an acryl-terminated terpolymer of dimethyl siloxane, diphenyl siloxane or phenylmethyl siloxane and 3,3,3-trifluoropropylmethyl siloxane. Preferably, said polysiloxanes comprise at least about 4 mol % of trifluoropropylmethyl siloxane and 1 to 50 mol % of diphenylsiloxane and/or phenylmethylsiloxane. More preferably said polysiloxanes comprise about 4 to 65 mol % trifluoropropylmethyl siloxane, 1 to 50 mol % of diphenylsiloxaue and dimethylsiloxane monomer units. One suitable acryl-terminated polysiloxane composition comprises about 28 mol % trifluoropropylmethyl siloxane, about 4 mol % diphenyl siloxane and dimethyl siloxane monomer units.
The invention also relates to an injectable lens material having a suitable viscosity to be injected through standard cannula with an 18 Gauge needle or finer. For this purpose the material should preferably have a viscosity lower than about 60 000 cSt or below about 8000 cSt for being readily injectable through a 21 Gauge needle. The injectable lens material is composition of at least one type of polysiloxanes according to any of the definitions above, a photoinitiator, optionally a crosslinking agent, which in itself can be siloxane oligoimer or polymer having functional acryl groups and further physiologically or ophthalmologically acceptable additives necessary for producing a lens. The composition is preferably formed as fluid mixture from separately stored constituents which are protected from reactivity during storage. This type of kits or multi-chamber cartridges with mixing equipment and their operation are well known in the art of pharmaceuticals or silicone products and will not be discussed here in further detail. To reduce physiological hazards, only acryl-substituted siloxane polymers are introduced into the capsular bag, together with medically acceptable photoinitiators activated in the visible range, including blue light activated types derived from acyl phosphine oxides and bisacylphosphine oxides, in low molecular weight and high molecular weight (polymeric) forms, and titianocene-photoinitiators. Important characteristics of these photoinitiators for injectable lens applications are that they initiate the photopolymerization of acryl groups when exposed to visible light, preferably blue light and that they are xe2x80x9cphotobleachingxe2x80x9d and so they are efficient as photoinitiators for the rapid curing of thick sections (1-5 mm). Suitable photoinitiators for injectable lens forming compositions are also discussed in WO 99/47185 and in the Swedish Patent Application No. 9900935-9 which both are incorporated herein as references. For the embodiment discussed in said Swedish Patent Application No. 9900935-9, wherein the photoinitiator is a conjugate of a photoactive groups and a macromolecule capable of participating in a crosslinking reaction with acryl-terminated polysiloxanes, the macromolecule in such a photocrosslinker should be a polysiloxane compatible with said first polysiloxanes. The injectable lens material composition can also comprise said polysiloxanes having functional acryl groups, a photoinitiator according to above and a separate crosslinking agent. Suitable crosslinking agents can be found among di- or tri- and higher order acrylates, methacrylates, acrylamides, methacrylamides including siloxane oligomers and polymers having functional acryl groups. Short molecule crosslinkers are exemplified by hexanediol acrylate, tripropyleneglycol diacrylate. Polymeric crosslinkers, suitable for injectable IOL applications are exemplified by copolymers or higher order polymers incorporating (methacryloxypropyl)methylsiloxane units.
Further, the invention relates to a method of producing an elastomer, preferably an intraocular lens, by preparing polysiloxane copolymers with functional acryl groups as previously defined, mixing said copolymers with a photoinitiator and optionally a crosslinking agent, injecting said mixture into a lens forming mold, irradiating the injected mixture with light so as to form the solid elastomer. Most preferably, according to the present invention the mixture is injected into the human eye to form an implant to replace the natural lens, but the method is also conceivable in non-surgical processes, such as conventional lens manufacturing with injection molding.
A method of in vivo production of an intraocular lens, will comprise the steps of preparing an polysiloxane copolymer having functional acryl groups according to the invention; mixing said copolymer and a photoinitiator, preferably a medically acceptable blue light photoinitiator, to a composition; injecting said composition comprising said copolymer and photoinitiator into the capsular bag of the eye; and initiating a polymerization reaction to create a lens in the capsular bag.
The invention also relates to an elastomer manufactured by the process described above. Preferably, such an elastomer is in the form of an optical lens, which preferably has a refractive index between 1.39 and 1.46, or, more preferably, close to 1.41. To obtain optical lenses having the desired refractive index, the proportions between the copolymer precursors should preferably be close to the proportions demonstrated in the Examples given below. However, as mentioned above it is possible to obtain higher lenses with higher refractive indices up to about 1.60 according to the present invention if this is necessary to obtain specific refraction values in certain clinical applications. Further, by employing the polysiloxanes with functional acryl groups, the injectable material and the methods of the present invention lenses with a compression modulus suitable to undergo accommodation by the forces of the eye can be obtained. Typically, lenses having a modulus below about 55 kPa and in the range of about 20 to 50 kPa can readily be obtained by employing the present invention which are functionally accommodatable by the human eye. Optionally, the elastomer according to the invention can also comprise an UV absorbing compound or other conventional additives known to those skilled in the art.
The invention further relates to a medicinal kit consisting of part (a) comprising polysiloxane copolymers having functional acryl groups according to the invention; and a part (b) comprising a clinically acceptable photoinitiator. The combination gives liquid silicone polymers of controlled photo-reactivity that can be xe2x80x9ccommand setxe2x80x9d by photopolymerization, upon exposure to blue light. The specification of this photo-crosslinkable system derives from an interplay of the viscosity and the injection density of the initial polymer solution, as well as the refractive index, modulus and compressive characteristics of the photocured gel.
A special advantage of the materials of this invention is that the incorporation of a fluoroalkyl siloxane enables materials of higher specific gravity to be produced than has previously been reported in silicones for ophthalmic use. Polydimethylsiloxane (PDMS), having refractive index 1.403 and specific gravity ca. 0.97-0.98, has been reported as a material for an injectable IOL. However, whilst the refractive index of PDMS approximately matches that of the human lens, the lower specific gravity of PDMS can present considerable difficulty for the surgeon as PDMS floats in aqueous solution. This makes complete filling of the capsular bag with exclusion of aqueous fluid difficult in the case of direct injection. Copolymers of dimethyl and diphenyl siloxanes have higher specific gravity than PDMS. However, the diphenyl content of the copolymers increases the refractive index, thus, for example, it is not possible to have a dimethyl-diphenyl copolymer with a specific gravity greater than 1.0 and a refractive index of less than approximately 1.44. Materials of the present invention, being copolymers, terpolymers or higher order polymers, incorporating fluoroalkyl siloxane units, enable silicones of specific gravity greater than 1.0 to be produced over a wider range of refractive index than has previously been reported.
The following examples aim to illustrate methods of preparing polysiloxanes having functional acryl groups and their subsequent photopolymerization. The preparation of acryl terminated siloxanes in general has been well reported (see Thomas, D. R.: p.610 in xe2x80x9cSiloxane Polymersxe2x80x9d (Clarson, S. J. and Semlyen. J. A., eds.) New Jersey, 1993) and the examples given below are those preferred of the many routes. The preparation of acrylic terminated terpolymers of dimethylsiloxane/diphenyl-siloxane/methyl,3,3,3-trifluoropropylsiloxane have not been reported.